Scandinavian Journal of Gastroenterology. 2014; 49: 853–861
ORIGINAL ARTICLE
Predicting the invasion depth of esophageal squamous cell carcinoma: comparison of endoscopic ultrasonography and magnifying endoscopy
MOON WON LEE1, GWANG HA KIM1, HOSEOK I2, DO YOUN PARK3, DONG HOON BAEK1, BONG EUN LEE1 & GEUN AM SONG1 1
Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea, 2Department of Chest Surgery, Pusan National University School of Medicine, Busan, Korea, and 3Department of Pathology, Pusan National University School of Medicine, Busan, Korea
Abstract Objective. Predicting the invasion depth of superficial esophageal squamous cell carcinoma (SESCC) is important when selecting among therapeutic strategies. The aim of this study was to compare magnifying endoscopy with narrow-band imaging (ME-NBI) with endoscopic ultrasonography (EUS) for predicting the depth of tumor invasion in patients with SESCC. Methods. This study enrolled 51 patients with SESCC (52 SESCC lesions) who underwent both ME-NBI and EUS at Pusan National University Hospital during 2010–2013. We reviewed the patients’ medical records and compared ME-NBI and EUS findings with histopathological results according to clinicopathological factors. Results. A total of 46 lesions in 45 patients were included in the final analysis. ME-NBI and EUS had overall accuracies of 76.1% and 84.8%, respectively, in distinguishing mucosal from non-mucosal cancers. There were no differences between ME-NBI and EUS in terms of sensitivities and specificities in distinguishing mucosal from non-mucosal cancers (p = 0.500 and p = 0.688, respectively). When both ME-NBI and EUS suggested a mucosal depth of lesion invasion, the frequency of mucosal cancer in the final histopathology was 94%. However, if either ME-NBI or EUS suggested a non-mucosal depth of invasion, the frequency of mucosal cancer was only 21%. Conclusion. ME-NBI and EUS are accurate predictors of SESCC invasion depth. If both methods suggest a mucosal depth of lesion invasion, the accuracy of the prediction is increased. Therefore, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection.
Key Words: diagnosis, endoscopic ultrasonography, esophageal squamous cell carcinoma, magnifying endoscopy
Introduction Superficial esophageal squamous cell carcinoma (SESCC) is defined as squamous cell carcinoma (SCC) in which infiltration is confined to the mucosa or submucosa [1,2]. The recent development of endoscopic diagnostic techniques using iodine staining and narrow-band imaging (NBI) has been accompanied by an increase in the incidence of SESCC. Traditionally, esophagectomy with lymph node (LN) dissection has been the treatment of choice for most cases of
esophageal cancer, even for cancers that are limited to the mucosa [3]. However, surgery is generally associated with high mortality and morbidity rates [4,5]. Further, surgery cannot be performed in a considerable proportion of patients because of the patient’s advanced age or the presence of comorbidities [6,7]. In these situations, endoscopic treatments, such as endoscopic submucosal dissection, may offer alternatives to esophagectomy for early stage esophageal cancer [8,9]. Because endoscopic treatment is primarily indicated for patients with a low risk of LN metastasis, identifying
Correspondence: Gwang Ha Kim, MD, Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, 179, Gudeok-ro, Seo-Gu, Busan 602-739, Korea. Tel: +82 51 240 7869. Fax: +82 51 244 8180. E-mail: [email protected]
(Received 10 January 2014; revised 7 April 2014; accepted 10 April 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.915052
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such patients is particularly important [4,10]. The invasion depth of SESCC is an especially important factor when selecting a therapeutic strategy because the frequency of LN metastasis increases in proportion to the depth of tumor invasion in the esophageal wall. Indeed, although the risk of LN metastasis is 0–3% among SESCCs confined to the mucosa, it reaches 15– 50% when the submucosa has been invaded [11,12]. Therefore, when selecting patients for local endoscopic resection, it is crucial to distinguish between mucosal cancers and non-mucosal cancers that have infiltrated the submucosal or deeper layers. Endoscopic ultrasonography (EUS) is the most accurate method available for staging esophageal carcinoma in terms of both depth of invasion (T stage) and presence or absence of involved LNs (N stage) [13]. Additionally, EUS using a high-frequency catheter probe provides a high level of diagnostic accuracy in distinguishing mucosal from submucosal esophageal cancers [14,15]. However, EUS using a high-frequency catheter probe also has several limitations, such as the difficulty of filling the esophageal lumen with water, or inappropriate positioning of the probe owing to anatomical locations (e.g., in the lower esophagus near the esophagogastric junction), causing pseudo-thickening and a poor view of the layers [16–18]. Recent advances in magnifying endoscopy (ME) have enabled the production of high-resolution images with high pixel densities, permitting assessments of microvascular patterns of the esophageal mucosa [19]. Further, new image-enhanced endoscopy techniques, such as ME with NBI (ME-NBI), enable clearer observation of microvessels [20]. The intrapapillary capillary loop (IPCL) is generally defined as the superficial fine vascular network of the esophageal mucosa [2]. ME-NBI has allowed detailed observations of IPCLs, and the invasion depth of SESCC is estimated from the degree of destruction of the IPCLs [21,22]. To date, however, few studies have examined the comparative accuracies of ME-NBI and EUS for predicting the invasion depth of SESCC [23]. Therefore, the aim of this study was to compare the abilities of ME-NBI and EUS for predicting the depth of tumor invasion in patients with SESCC.
lesions in 51 patients with endoscopically suspected SESCC. All lesions were histologically diagnosed as SCC by endoscopic biopsy. None of the patients had previously received chemotherapy or radiotherapy. This study was reviewed and approved by the Institutional Review Board of Pusan National University Hospital. Magnifying endoscopy with narrow-band imaging The video endoscopy system used was the EVISLUCERA SPECTRUM system (Olympus Medical Systems Corp., Tokyo, Japan), which consisted of a light source (CLV-260SL), a processor (CV-260SL) and a magnifying video endoscope (GIF-H260Z). The system was capable of both white light and NBI modes, which could be toggled in a few seconds using a button on the control head of the video endoscope. This endoscopy system has a zoom magnification of 80. To obtain a clear view with ME, a black soft hood (MB-46; Olympus Medical Systems) was fitted on the distal tip of the endoscope to maintain the focal distance. ME-NBI was performed by a single experienced endoscopist (G.H. Kim) who had previously performed more than 100 examinations. All examinations were performed under conscious sedation using 2–5 mg of midazolam, as is provided in conventional endoscopy. After routine observation, ME-NBI examinations of SCC areas were performed to evaluate microvascular patterns. Tumor invasion depth was determined using ME-NBI in accordance with the classification system described by Inoue et al. [19,21]. Under ME-NBI observation, normal IPCLs could be observed as single microvascular loops of the final branch of the arborescent vessels arising from the submucosal vein. Mucosal cancer was defined when irregular IPCLs with dilatation, tortuous running, caliber change or various shapes were independently formed into the shapes of dots or extensions, or when irregular IPCLs had communication with each IPCL (Figure 1). Submucosal cancer was defined when IPCLs had been destroyed or when we observed abnormal tumor vessels that showed shaggy formations with significantly irregular shape (Figure 2) [23]. Endoscopic ultrasonography
Methods We retrospectively analyzed a database of all patients with esophageal SCC who had undergone both ME-NBI and EUS for pretreatment staging at Pusan National University Hospital (Busan, Korea) between October 2010 and December 2013. Data for ME-NBI and EUS findings were prospectively collected during the examinations. We identified 52
EUS was performed with a radial scanning 20-MHz catheter probe (UM3D-DP20-25R, Olympus Medical Systems) using the jelly-filled method [24,25]. The probe was passed through one instrument channel of a 2-channel endoscope (GIF-2T240, Olympus Medical Systems) and 20–40 ml of echo jelly (Daejin Co. Ltd, Seoul, Korea) was instilled using a 10-Fr disposable oxygen catheter (HS-OC, Hyup Sung
EUS and magnifying endoscopy in esophageal cancer A
B
C
D
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Figure 1. A case of mucosal esophageal squamous cell carcinoma is shown. (A) Conventional endoscopy shows a reddish flat lesion in the midesophagus. (B) ME-NBI demonstrates that IPCLs are irregular but the looping structure remains conserved. (C) EUS using a high-frequency catheter probe shows that a hypoechoic lesion is confined to the mucosal layer. (D) Histology from endoscopic submucosal dissection shows a well differentiated squamous cell carcinoma confined to the mucosa (H&E stain, 100).
Medical Co. Ltd, Seoul, Korea) through the other instrument channel until the esophageal lumen was filled. All examinations were performed under intravenous conscious sedation (midazolam with or without meperidine) by a single experienced endoscopist (G.H. Kim) who had previously performed more than 1000 EUS examinations. The probe yielded high-quality cross-sectional images of the esophageal wall and was easily directed to the small cancer lesions under the direct vision of the endoscopist [15]. According to previous reports, the tumor depth on EUS images was interpreted as follows [20,26,27]. In a seven-layered image, the first, second, and third layers correspond to the epithelium plus the interface echo, the lamina propria plus the muscularis mucosae, and the submucosa, respectively. Tumors without changes in the seven-layered structure or changes involving the first two layers (not including the third layer) were staged as mucosal carcinoma (Figure 1). Tumors
involving the first three layers without involvement of the fourth layer were staged as submucosal carcinoma (Figure 2). In a nine-layered image, the first, second, third, fourth, and fifth layers corresponded to the superficial epithelium plus the interface echo, the deep epithelium, the lamina propria plus the interface echo, the muscularis mucosae minus the interface echo, and the submucosa, respectively. Tumors without changes in the nine-layered structure or involving the first four layers without the fifth layer were staged as mucosal carcinoma. Tumors involving the first five layers but not the sixth layer were staged as submucosal carcinoma. The SESCCs were classified into three groups: mucosal, submucosal, or advanced. Clinicopathological review Endoscopic resection or esophagectomy was performed within the 2 4 weeks following ME-NBI
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B
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Figure 2. A case of submucosal esophageal squamous cell carcinoma is shown. (A) Conventional endoscopy shows a reddish elevated lesion with a depressed area in the mid-esophagus. (B) ME-NBI demonstrates that abnormal tumor vessels with significantly irregular shapes appear at the area where the looping structure is destroyed. (C) EUS using a high-frequency catheter probe shows a hypoechoic lesion infiltrating into the submucosal layer. (D) Histology from surgical resection reveals a squamous cell carcinoma with massive submucosal invasion (H&E stain, 40).
and EUS. The resected specimens were fixed in 10% formaldehyde. Carcinomas with adjacent nonneoplastic mucosa were serially cut into 2 mm slices in parallel and embedded in paraffin, and then sectioned and stained with hematoxylin-eosin for histological examination. Tumor location, macroscopic shape, circumferential spread, tumor size, tumor differentiation, and the depth of invasion were reviewed according to the World Health Organization recommendations [28]. The depth of invasion was classified as mucosal, submucosal, or advanced (the tumor had invaded the muscularis propria or deeper), according to the Japanese criteria [1].
using c2 tests or Fisher’s exact tests. Associations between ME-NBI and EUS in distinguishing mucosal from non-mucosal cancers were evaluated for sensitivity, specificity, and accuracy with 95% confidence interval (95% CI), and their differences were evaluated using McNemar’s exact test. Statistical calculations were performed using SPSS version 21.0 software for Windows (SPSS, Inc., Chicago, IL, USA). Results were considered statistically significant for all p-Values < 0.05. Results Demographic, endoscopic, and histologic characteristics
Statistical analysis The accuracies of ME-NBI and EUS in relation to clinicopathological characteristics were assessed
Of the 51 patients, 6 patients were excluded from the analyses because the final histological results were not available: 1 patient received chemotherapy because of
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with surgery and 11 lesions were treated with endoscopic resection. The characteristics of the lesions are summarized in Table I.
Table I. Baseline characteristics of 46 superficial esophageal squamous cell carcinomas in 45 patients. Characteristics
Number (%)
Male/female (n = 45) Mean age, years (range) Location Upper esophagus Mid-esophagus Lower esophagus Macroscopic shape Elevated Flat Depressed Mean tumor size, mm (range) Circumferential spread 3 cm. Histopathologically, there were 23 mucosal cancers, 20 submucosal cancers, and 3 advanced cancers. A total of 35 lesions were treated
Table II. ME-NBI and EUS assessments of lesion depth for superficial esophageal carcinoma. Histopathology
ME-NBI Mucosa Submucosa EUS Mucosa Submucosa Advanced
No.
Mucosa
Submucosa
Advanced
22 24
17 6
5 15
0 3
22 23 1
19 4 0
3 17 0
0 2 1
Accuracy in distinguishing mucosal from non-mucosal cancers 35/46 (76.1%)
39/46 (84.8%)
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
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Table III. Accuracy of ME-NBI and EUS in distinguishing mucosal from non-mucosal cancers in cases of superficial esophageal carcinoma, according to clinicopathological characteristics. ME-NBI No. of accurately assessed lesions (%)
Characteristics Location Upper esophagus Mid-esophagus Lower esophagus Macroscopic shape Elevated Flat Depressed Circumferential spread 3 cm
EUS p-Value
No. of accurately assessed lesions (%)
p-Value
1.000 2/2 (100) 27/36 (75.0) 6/8 (75.0)
0.709 2/2 (100) 31/36 (86.1) 6/8 (75.0)
0.667 11/15 (73.3) 18/22 (81.8) 6/9 (66.7)
0.570 12/15 (80.0) 20/22 (90.9) 7/9 (77.8)
0.415 13/15 12/19 7/9 3/3
(86.7) (63.2) (77.8) (100)
0.130 15/15 14/19 7/9 3/3
(100) (73.7) (77.8) (100)
0.276 15/18 (83.3) 15/23 (65.2) 5/5 (100)
0.334 17/18 (94.4) 18/23 (78.3) 4/5 (80.0)
1.000 25/33 (75.8) 10/13 (76.9)
1.000 28/33 (84.8) 11/13 (84.6)
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
Table IV. Sensitivities, specificities, and accuracies of ME-NBI and EUS assessments in distinguishing mucosal from non-mucosal cancers in cases of superficial esophageal carcinoma.
Sensitivity (%) (95% CI) Specificity (%) (95% CI) Accuracy (%) (95% CI)
ME-NBI
EUS
p-Value
73.9 (56.0, 91.8) 78.3 (61.5, 95.1) 76.1 (63.8, 88.4)
82.6 (67.1, 98.1) 87.0 (73.3, 100) 84.8 (74.4, 95.2)
0.500 0.688 0.289
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
was 94% (17/18) (Table V). However, if either ME-NBI or EUS suggested that the invasion depth was non-mucosal, the frequency of mucosal cancer was only 21% (6/28). Discussion Generally, EUS has been considered the method of examination that most accurately predicts the invasion depth of SESCC [29,30]. Several recent studies,
mainly in Japan, have demonstrated that ME-NBI also provides a useful method for estimating superficial tumor depth [22,23,31]. Naturally, the key question is, “Which method is more accurate?” To date, few reports have on compared the abilities of ME-NBI and EUS for predicting the invasion depth of SESCC [23]. In the present study, the accuracies of ME-NBI and EUS in distinguishing mucosal from non-mucosal cancers were 76.1% and 84.8%, respectively. We found no significant differences between
Table V. Frequencies of mucosal cancer in histopathological diagnoses according to combination of ME-NBI and EUS assessments. Diagnostic methods ME-NBI
EUS
Mucosal cancer Mucosal cancer Non-mucosal cancer Non-mucosal cancer
Mucosal cancer Non-mucosal cancer Mucosal cancer Non-mucosal cancer
No. of lesion
No. of mucosal cancer in histopathological diagnosis (%)
18 4 4 20
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
17 0 2 4
(94%) (0%) (50%) (20%)
EUS and magnifying endoscopy in esophageal cancer ME-NBI and EUS in terms of sensitivities and specificities. Currently, EUS is considered the best available technique for defining locally advanced, potentially curable lesions in patients with carcinomas of the esophagus or esophagogastric junction. In a recent meta-analysis, for suspected early stage esophageal cancer, EUS is recommended first to rule out infiltration of the muscularis propria and regional LN metastasis, followed by endoscopic resection with histological examination of the resection specimen as the diagnostic algorithm for evaluating superficial esophageal cancer [32]. In the present study, EUS conducted with a high-frequency (20 MHz) catheter probe accurately identified the depth of SESCC invasion in 80.4% (37/46) of the cases. In addition, the overall accuracy of EUS in distinguishing mucosal from non-mucosal cancers was 84.8% (39/46). Accordingly, our data confirm the usefulness of EUS in distinguishing tumors invading the mucosa from those infiltrating the submucosa – a result that is consistent with several previous studies [11,14,15,26,33]. Therefore, we recommend that EUS, especially using a high-frequency catheter probe, be used to determine the patients with mucosal SCC who are appropriate for endoscopic resection as well as to rule out those with infiltration of the muscularis propria and regional LN metastasis. In the present study, EUS overestimated the invasion depth of 4 of the 46 lesions (8.7%). This result is also similar to the findings of previous studies [17,23]. Overestimation of invasion depth in EUS can be attributed to the following factors [17,18]: (1) peritumoral inflammation, which leads to wall thickening and thereby making it difficult to distinguish the different layers; (2) inappropriate positioning of the ultrasound transducer owing to its anatomical location (e.g., in the lower esophagus near the esophagogastric junction), which leads to pseudothickening and a poor view of the layers; and (3) use of the water-filled balloon method. In the present study, we used a jelly-filled method, which is characterized by filling the esophageal lumen with jelly that enables convenient observations without the use of a balloon [15]. This jelly-filled method could overcome the problems that arise when conducting EUS with a water-filled balloon [34,35] or a device for continuous water instillation [36,37]. In fact, when using a waterfilled balloon method, the balloon sheath can compress the lesion to the submucosa, potentially making the mucosal cancer appear similar to a submucosal cancer [26]. Further, attempts to inflate the esophagus using a continuous instillation of water may increase the risk of aspiration. Accordingly, it is not easy to dilate the lumen adequately in the lower
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esophagus, specifically because of the frequent passage of EUS medium into the stomach [16]. As a result, the overestimation rate in our study (8.7%) was somewhat lower than that (18.6%) observed in a study that used a water-filled balloon method [18], and there were no differences according to tumor location. In addition, two of the four overestimated lesions were histologically demonstrated to have inflammatory changes that accompanied the tumor. EUS underestimated the invasion depth in 5 of 46 lesions (10.9%) in the present study. Underestimation can be attributed to the following factors [28]: (1) tumor location near the esophagogastric junction and (2) minute submucosal invasion, which is also known as sm1 cancer. If the tumor is located near the esophagogastric junction, there is a risk of underestimation because of the technical difficulty of EUS at this location. As discussed in the paragraph above, this difficulty could be overcome in the present study by using the jelly-filled method. Because the resolution of EUS is approximately 200 mm with a 20-MHz probe [38], minute submucosal invasive cancer is difficult to diagnose. Indeed, of the four sm1 cancers in the present study, two were underestimated. In the present study, the accuracy rate of ME-NBI in differentiating mucosal cancer from non-mucosal cancer was 76.1%, which is similar to the results of previous studies [22,31]. In this study, we analyzed ME-NBI findings of SESCC using Inoue’s classification. However, there are no gold standard criteria for ME-NBI findings of SESCC. Inoue’s classification is based on the pattern of IPCLs. An alternative classification, Arima’s classification, incorporates the size of the avascular area in addition to the patterns of IPCLs [39]. In a recent study that compared these classifications, the specificity of predicted invasion depth was higher for Arima’s classification than it was for Inoue’s classification [31]. However, Arima’s classification was more complicated than Inoue’s classification, and its interobserver concordance rate was lower than that of Inoue’s classification [31]. Before our study, no report had examined the factors that influence the accuracy of ME-NBI. We found no clinicopathological factors that influenced the accuracy of ME-NBI. The rates of overestimation and underestimation were 13.0% and 10.9% for ME-NBI, which are slightly higher than those observed in a previous study [23]. In that study, the overestimation and underestimation rates of ME-NBI were 80% of the tumors included in that study were mucosal cancers. On the other hand, 50% of tumors included in our study were submucosal cancers. We believe that these differences in the proportions of mucosal
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and non-mucosal cancers account for the higher rate of underestimation in our study. Although there were no significant differences between ME-NBI and EUS in terms of sensitivities and specificities, the sensitivity and specificity rates tended to be higher for EUS. Therefore, EUS might be more suitable for identifying mucosal carcinomas that are likely to be indicated for endoscopic resection. In fact, our study showed that if both ME-NBI and EUS suggested a mucosal depth of SESCC invasion, the probability of mucosal cancer in the final histopathological assessment was very high (94%). Therefore, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection. In this manner, unnecessary endoscopic treatments could be avoided. However, before using the combination of ME-NBI and EUS in clinical practice for patients with SESCC, prospective studies are needed to evaluate the additive benefit of these techniques in predicting the invasion depth of SESCC. This study had several limitations. First, the majority of ME-NBI and EUS examinations were performed in a fixed order by the same endoscopist. Consequently, the results of ME-NBI could affect the interpretation of EUS findings. Ideally, it would be better to perform EUS and ME-NBI in a randomized order. In practice, however, it is very difficult to perform ME-NBI after EUS because the jelly used for EUS hinders detailed examinations with ME-NBI. Second, EUS and ME-NBI were performed by a single experienced endoscopist, and interobserver variation was not evaluated. Although interobserver agreement has been reported to be reliable in both EUS using a jelly-filled method and ME-NBI [15,31,40,41], interobserver variability in the assessments of EUS and ME-NBI needs to be evaluated before clinical application. In the future, a randomized, blinded crossover trial that includes the interobserver variation will be needed to determine the superior method for predicting the invasion depth of SESCC. Third, in addition to the assessment of invasion depth, EUS plays an important role in the evaluation of potential LN metastasis [13]. However, in this study, as we focused on comparing the use of ME-NBI with that of EUS for predicting the depth of tumor invasion, we used only a 20-MHz probe for EUS. Therefore, we could not evaluate LN metastasis accurately because of the limited depth of penetration of this 20-MHz probe. In conclusion, both ME-NBI and EUS provide accurate methods of predicting the invasion depth of SESCC. Their accuracies do not differ. However, when both ME-NBI and EUS suggest that the
invasion depth of the lesion is mucosal, the accuracy of the prediction is increased. Therefore, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection.
Acknowledgements This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (0920050) and by a clinical research grant from Pusan National University Hospital 2014. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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ORIGINAL ARTICLE
Predicting the invasion depth of esophageal squamous cell carcinoma: comparison of endoscopic ultrasonography and magnifying endoscopy
MOON WON LEE1, GWANG HA KIM1, HOSEOK I2, DO YOUN PARK3, DONG HOON BAEK1, BONG EUN LEE1 & GEUN AM SONG1 1
Department of Internal Medicine, Pusan National University School of Medicine, Busan, Korea, 2Department of Chest Surgery, Pusan National University School of Medicine, Busan, Korea, and 3Department of Pathology, Pusan National University School of Medicine, Busan, Korea
Abstract Objective. Predicting the invasion depth of superficial esophageal squamous cell carcinoma (SESCC) is important when selecting among therapeutic strategies. The aim of this study was to compare magnifying endoscopy with narrow-band imaging (ME-NBI) with endoscopic ultrasonography (EUS) for predicting the depth of tumor invasion in patients with SESCC. Methods. This study enrolled 51 patients with SESCC (52 SESCC lesions) who underwent both ME-NBI and EUS at Pusan National University Hospital during 2010–2013. We reviewed the patients’ medical records and compared ME-NBI and EUS findings with histopathological results according to clinicopathological factors. Results. A total of 46 lesions in 45 patients were included in the final analysis. ME-NBI and EUS had overall accuracies of 76.1% and 84.8%, respectively, in distinguishing mucosal from non-mucosal cancers. There were no differences between ME-NBI and EUS in terms of sensitivities and specificities in distinguishing mucosal from non-mucosal cancers (p = 0.500 and p = 0.688, respectively). When both ME-NBI and EUS suggested a mucosal depth of lesion invasion, the frequency of mucosal cancer in the final histopathology was 94%. However, if either ME-NBI or EUS suggested a non-mucosal depth of invasion, the frequency of mucosal cancer was only 21%. Conclusion. ME-NBI and EUS are accurate predictors of SESCC invasion depth. If both methods suggest a mucosal depth of lesion invasion, the accuracy of the prediction is increased. Therefore, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection.
Key Words: diagnosis, endoscopic ultrasonography, esophageal squamous cell carcinoma, magnifying endoscopy
Introduction Superficial esophageal squamous cell carcinoma (SESCC) is defined as squamous cell carcinoma (SCC) in which infiltration is confined to the mucosa or submucosa [1,2]. The recent development of endoscopic diagnostic techniques using iodine staining and narrow-band imaging (NBI) has been accompanied by an increase in the incidence of SESCC. Traditionally, esophagectomy with lymph node (LN) dissection has been the treatment of choice for most cases of
esophageal cancer, even for cancers that are limited to the mucosa [3]. However, surgery is generally associated with high mortality and morbidity rates [4,5]. Further, surgery cannot be performed in a considerable proportion of patients because of the patient’s advanced age or the presence of comorbidities [6,7]. In these situations, endoscopic treatments, such as endoscopic submucosal dissection, may offer alternatives to esophagectomy for early stage esophageal cancer [8,9]. Because endoscopic treatment is primarily indicated for patients with a low risk of LN metastasis, identifying
Correspondence: Gwang Ha Kim, MD, Department of Internal Medicine, Pusan National University School of Medicine and Biomedical Research Institute, Pusan National University Hospital, 179, Gudeok-ro, Seo-Gu, Busan 602-739, Korea. Tel: +82 51 240 7869. Fax: +82 51 244 8180. E-mail: [email protected]
(Received 10 January 2014; revised 7 April 2014; accepted 10 April 2014) ISSN 0036-5521 print/ISSN 1502-7708 online 2014 Informa Healthcare DOI: 10.3109/00365521.2014.915052
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such patients is particularly important [4,10]. The invasion depth of SESCC is an especially important factor when selecting a therapeutic strategy because the frequency of LN metastasis increases in proportion to the depth of tumor invasion in the esophageal wall. Indeed, although the risk of LN metastasis is 0–3% among SESCCs confined to the mucosa, it reaches 15– 50% when the submucosa has been invaded [11,12]. Therefore, when selecting patients for local endoscopic resection, it is crucial to distinguish between mucosal cancers and non-mucosal cancers that have infiltrated the submucosal or deeper layers. Endoscopic ultrasonography (EUS) is the most accurate method available for staging esophageal carcinoma in terms of both depth of invasion (T stage) and presence or absence of involved LNs (N stage) [13]. Additionally, EUS using a high-frequency catheter probe provides a high level of diagnostic accuracy in distinguishing mucosal from submucosal esophageal cancers [14,15]. However, EUS using a high-frequency catheter probe also has several limitations, such as the difficulty of filling the esophageal lumen with water, or inappropriate positioning of the probe owing to anatomical locations (e.g., in the lower esophagus near the esophagogastric junction), causing pseudo-thickening and a poor view of the layers [16–18]. Recent advances in magnifying endoscopy (ME) have enabled the production of high-resolution images with high pixel densities, permitting assessments of microvascular patterns of the esophageal mucosa [19]. Further, new image-enhanced endoscopy techniques, such as ME with NBI (ME-NBI), enable clearer observation of microvessels [20]. The intrapapillary capillary loop (IPCL) is generally defined as the superficial fine vascular network of the esophageal mucosa [2]. ME-NBI has allowed detailed observations of IPCLs, and the invasion depth of SESCC is estimated from the degree of destruction of the IPCLs [21,22]. To date, however, few studies have examined the comparative accuracies of ME-NBI and EUS for predicting the invasion depth of SESCC [23]. Therefore, the aim of this study was to compare the abilities of ME-NBI and EUS for predicting the depth of tumor invasion in patients with SESCC.
lesions in 51 patients with endoscopically suspected SESCC. All lesions were histologically diagnosed as SCC by endoscopic biopsy. None of the patients had previously received chemotherapy or radiotherapy. This study was reviewed and approved by the Institutional Review Board of Pusan National University Hospital. Magnifying endoscopy with narrow-band imaging The video endoscopy system used was the EVISLUCERA SPECTRUM system (Olympus Medical Systems Corp., Tokyo, Japan), which consisted of a light source (CLV-260SL), a processor (CV-260SL) and a magnifying video endoscope (GIF-H260Z). The system was capable of both white light and NBI modes, which could be toggled in a few seconds using a button on the control head of the video endoscope. This endoscopy system has a zoom magnification of 80. To obtain a clear view with ME, a black soft hood (MB-46; Olympus Medical Systems) was fitted on the distal tip of the endoscope to maintain the focal distance. ME-NBI was performed by a single experienced endoscopist (G.H. Kim) who had previously performed more than 100 examinations. All examinations were performed under conscious sedation using 2–5 mg of midazolam, as is provided in conventional endoscopy. After routine observation, ME-NBI examinations of SCC areas were performed to evaluate microvascular patterns. Tumor invasion depth was determined using ME-NBI in accordance with the classification system described by Inoue et al. [19,21]. Under ME-NBI observation, normal IPCLs could be observed as single microvascular loops of the final branch of the arborescent vessels arising from the submucosal vein. Mucosal cancer was defined when irregular IPCLs with dilatation, tortuous running, caliber change or various shapes were independently formed into the shapes of dots or extensions, or when irregular IPCLs had communication with each IPCL (Figure 1). Submucosal cancer was defined when IPCLs had been destroyed or when we observed abnormal tumor vessels that showed shaggy formations with significantly irregular shape (Figure 2) [23]. Endoscopic ultrasonography
Methods We retrospectively analyzed a database of all patients with esophageal SCC who had undergone both ME-NBI and EUS for pretreatment staging at Pusan National University Hospital (Busan, Korea) between October 2010 and December 2013. Data for ME-NBI and EUS findings were prospectively collected during the examinations. We identified 52
EUS was performed with a radial scanning 20-MHz catheter probe (UM3D-DP20-25R, Olympus Medical Systems) using the jelly-filled method [24,25]. The probe was passed through one instrument channel of a 2-channel endoscope (GIF-2T240, Olympus Medical Systems) and 20–40 ml of echo jelly (Daejin Co. Ltd, Seoul, Korea) was instilled using a 10-Fr disposable oxygen catheter (HS-OC, Hyup Sung
EUS and magnifying endoscopy in esophageal cancer A
B
C
D
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Figure 1. A case of mucosal esophageal squamous cell carcinoma is shown. (A) Conventional endoscopy shows a reddish flat lesion in the midesophagus. (B) ME-NBI demonstrates that IPCLs are irregular but the looping structure remains conserved. (C) EUS using a high-frequency catheter probe shows that a hypoechoic lesion is confined to the mucosal layer. (D) Histology from endoscopic submucosal dissection shows a well differentiated squamous cell carcinoma confined to the mucosa (H&E stain, 100).
Medical Co. Ltd, Seoul, Korea) through the other instrument channel until the esophageal lumen was filled. All examinations were performed under intravenous conscious sedation (midazolam with or without meperidine) by a single experienced endoscopist (G.H. Kim) who had previously performed more than 1000 EUS examinations. The probe yielded high-quality cross-sectional images of the esophageal wall and was easily directed to the small cancer lesions under the direct vision of the endoscopist [15]. According to previous reports, the tumor depth on EUS images was interpreted as follows [20,26,27]. In a seven-layered image, the first, second, and third layers correspond to the epithelium plus the interface echo, the lamina propria plus the muscularis mucosae, and the submucosa, respectively. Tumors without changes in the seven-layered structure or changes involving the first two layers (not including the third layer) were staged as mucosal carcinoma (Figure 1). Tumors
involving the first three layers without involvement of the fourth layer were staged as submucosal carcinoma (Figure 2). In a nine-layered image, the first, second, third, fourth, and fifth layers corresponded to the superficial epithelium plus the interface echo, the deep epithelium, the lamina propria plus the interface echo, the muscularis mucosae minus the interface echo, and the submucosa, respectively. Tumors without changes in the nine-layered structure or involving the first four layers without the fifth layer were staged as mucosal carcinoma. Tumors involving the first five layers but not the sixth layer were staged as submucosal carcinoma. The SESCCs were classified into three groups: mucosal, submucosal, or advanced. Clinicopathological review Endoscopic resection or esophagectomy was performed within the 2 4 weeks following ME-NBI
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B
C
D
Figure 2. A case of submucosal esophageal squamous cell carcinoma is shown. (A) Conventional endoscopy shows a reddish elevated lesion with a depressed area in the mid-esophagus. (B) ME-NBI demonstrates that abnormal tumor vessels with significantly irregular shapes appear at the area where the looping structure is destroyed. (C) EUS using a high-frequency catheter probe shows a hypoechoic lesion infiltrating into the submucosal layer. (D) Histology from surgical resection reveals a squamous cell carcinoma with massive submucosal invasion (H&E stain, 40).
and EUS. The resected specimens were fixed in 10% formaldehyde. Carcinomas with adjacent nonneoplastic mucosa were serially cut into 2 mm slices in parallel and embedded in paraffin, and then sectioned and stained with hematoxylin-eosin for histological examination. Tumor location, macroscopic shape, circumferential spread, tumor size, tumor differentiation, and the depth of invasion were reviewed according to the World Health Organization recommendations [28]. The depth of invasion was classified as mucosal, submucosal, or advanced (the tumor had invaded the muscularis propria or deeper), according to the Japanese criteria [1].
using c2 tests or Fisher’s exact tests. Associations between ME-NBI and EUS in distinguishing mucosal from non-mucosal cancers were evaluated for sensitivity, specificity, and accuracy with 95% confidence interval (95% CI), and their differences were evaluated using McNemar’s exact test. Statistical calculations were performed using SPSS version 21.0 software for Windows (SPSS, Inc., Chicago, IL, USA). Results were considered statistically significant for all p-Values < 0.05. Results Demographic, endoscopic, and histologic characteristics
Statistical analysis The accuracies of ME-NBI and EUS in relation to clinicopathological characteristics were assessed
Of the 51 patients, 6 patients were excluded from the analyses because the final histological results were not available: 1 patient received chemotherapy because of
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with surgery and 11 lesions were treated with endoscopic resection. The characteristics of the lesions are summarized in Table I.
Table I. Baseline characteristics of 46 superficial esophageal squamous cell carcinomas in 45 patients. Characteristics
Number (%)
Male/female (n = 45) Mean age, years (range) Location Upper esophagus Mid-esophagus Lower esophagus Macroscopic shape Elevated Flat Depressed Mean tumor size, mm (range) Circumferential spread 3 cm. Histopathologically, there were 23 mucosal cancers, 20 submucosal cancers, and 3 advanced cancers. A total of 35 lesions were treated
Table II. ME-NBI and EUS assessments of lesion depth for superficial esophageal carcinoma. Histopathology
ME-NBI Mucosa Submucosa EUS Mucosa Submucosa Advanced
No.
Mucosa
Submucosa
Advanced
22 24
17 6
5 15
0 3
22 23 1
19 4 0
3 17 0
0 2 1
Accuracy in distinguishing mucosal from non-mucosal cancers 35/46 (76.1%)
39/46 (84.8%)
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
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Table III. Accuracy of ME-NBI and EUS in distinguishing mucosal from non-mucosal cancers in cases of superficial esophageal carcinoma, according to clinicopathological characteristics. ME-NBI No. of accurately assessed lesions (%)
Characteristics Location Upper esophagus Mid-esophagus Lower esophagus Macroscopic shape Elevated Flat Depressed Circumferential spread 3 cm
EUS p-Value
No. of accurately assessed lesions (%)
p-Value
1.000 2/2 (100) 27/36 (75.0) 6/8 (75.0)
0.709 2/2 (100) 31/36 (86.1) 6/8 (75.0)
0.667 11/15 (73.3) 18/22 (81.8) 6/9 (66.7)
0.570 12/15 (80.0) 20/22 (90.9) 7/9 (77.8)
0.415 13/15 12/19 7/9 3/3
(86.7) (63.2) (77.8) (100)
0.130 15/15 14/19 7/9 3/3
(100) (73.7) (77.8) (100)
0.276 15/18 (83.3) 15/23 (65.2) 5/5 (100)
0.334 17/18 (94.4) 18/23 (78.3) 4/5 (80.0)
1.000 25/33 (75.8) 10/13 (76.9)
1.000 28/33 (84.8) 11/13 (84.6)
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
Table IV. Sensitivities, specificities, and accuracies of ME-NBI and EUS assessments in distinguishing mucosal from non-mucosal cancers in cases of superficial esophageal carcinoma.
Sensitivity (%) (95% CI) Specificity (%) (95% CI) Accuracy (%) (95% CI)
ME-NBI
EUS
p-Value
73.9 (56.0, 91.8) 78.3 (61.5, 95.1) 76.1 (63.8, 88.4)
82.6 (67.1, 98.1) 87.0 (73.3, 100) 84.8 (74.4, 95.2)
0.500 0.688 0.289
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
was 94% (17/18) (Table V). However, if either ME-NBI or EUS suggested that the invasion depth was non-mucosal, the frequency of mucosal cancer was only 21% (6/28). Discussion Generally, EUS has been considered the method of examination that most accurately predicts the invasion depth of SESCC [29,30]. Several recent studies,
mainly in Japan, have demonstrated that ME-NBI also provides a useful method for estimating superficial tumor depth [22,23,31]. Naturally, the key question is, “Which method is more accurate?” To date, few reports have on compared the abilities of ME-NBI and EUS for predicting the invasion depth of SESCC [23]. In the present study, the accuracies of ME-NBI and EUS in distinguishing mucosal from non-mucosal cancers were 76.1% and 84.8%, respectively. We found no significant differences between
Table V. Frequencies of mucosal cancer in histopathological diagnoses according to combination of ME-NBI and EUS assessments. Diagnostic methods ME-NBI
EUS
Mucosal cancer Mucosal cancer Non-mucosal cancer Non-mucosal cancer
Mucosal cancer Non-mucosal cancer Mucosal cancer Non-mucosal cancer
No. of lesion
No. of mucosal cancer in histopathological diagnosis (%)
18 4 4 20
Abbreviations: EUS: Endoscopic ultrasonography; ME-NBI: Magnifying endoscopy with narrow-band imaging.
17 0 2 4
(94%) (0%) (50%) (20%)
EUS and magnifying endoscopy in esophageal cancer ME-NBI and EUS in terms of sensitivities and specificities. Currently, EUS is considered the best available technique for defining locally advanced, potentially curable lesions in patients with carcinomas of the esophagus or esophagogastric junction. In a recent meta-analysis, for suspected early stage esophageal cancer, EUS is recommended first to rule out infiltration of the muscularis propria and regional LN metastasis, followed by endoscopic resection with histological examination of the resection specimen as the diagnostic algorithm for evaluating superficial esophageal cancer [32]. In the present study, EUS conducted with a high-frequency (20 MHz) catheter probe accurately identified the depth of SESCC invasion in 80.4% (37/46) of the cases. In addition, the overall accuracy of EUS in distinguishing mucosal from non-mucosal cancers was 84.8% (39/46). Accordingly, our data confirm the usefulness of EUS in distinguishing tumors invading the mucosa from those infiltrating the submucosa – a result that is consistent with several previous studies [11,14,15,26,33]. Therefore, we recommend that EUS, especially using a high-frequency catheter probe, be used to determine the patients with mucosal SCC who are appropriate for endoscopic resection as well as to rule out those with infiltration of the muscularis propria and regional LN metastasis. In the present study, EUS overestimated the invasion depth of 4 of the 46 lesions (8.7%). This result is also similar to the findings of previous studies [17,23]. Overestimation of invasion depth in EUS can be attributed to the following factors [17,18]: (1) peritumoral inflammation, which leads to wall thickening and thereby making it difficult to distinguish the different layers; (2) inappropriate positioning of the ultrasound transducer owing to its anatomical location (e.g., in the lower esophagus near the esophagogastric junction), which leads to pseudothickening and a poor view of the layers; and (3) use of the water-filled balloon method. In the present study, we used a jelly-filled method, which is characterized by filling the esophageal lumen with jelly that enables convenient observations without the use of a balloon [15]. This jelly-filled method could overcome the problems that arise when conducting EUS with a water-filled balloon [34,35] or a device for continuous water instillation [36,37]. In fact, when using a waterfilled balloon method, the balloon sheath can compress the lesion to the submucosa, potentially making the mucosal cancer appear similar to a submucosal cancer [26]. Further, attempts to inflate the esophagus using a continuous instillation of water may increase the risk of aspiration. Accordingly, it is not easy to dilate the lumen adequately in the lower
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esophagus, specifically because of the frequent passage of EUS medium into the stomach [16]. As a result, the overestimation rate in our study (8.7%) was somewhat lower than that (18.6%) observed in a study that used a water-filled balloon method [18], and there were no differences according to tumor location. In addition, two of the four overestimated lesions were histologically demonstrated to have inflammatory changes that accompanied the tumor. EUS underestimated the invasion depth in 5 of 46 lesions (10.9%) in the present study. Underestimation can be attributed to the following factors [28]: (1) tumor location near the esophagogastric junction and (2) minute submucosal invasion, which is also known as sm1 cancer. If the tumor is located near the esophagogastric junction, there is a risk of underestimation because of the technical difficulty of EUS at this location. As discussed in the paragraph above, this difficulty could be overcome in the present study by using the jelly-filled method. Because the resolution of EUS is approximately 200 mm with a 20-MHz probe [38], minute submucosal invasive cancer is difficult to diagnose. Indeed, of the four sm1 cancers in the present study, two were underestimated. In the present study, the accuracy rate of ME-NBI in differentiating mucosal cancer from non-mucosal cancer was 76.1%, which is similar to the results of previous studies [22,31]. In this study, we analyzed ME-NBI findings of SESCC using Inoue’s classification. However, there are no gold standard criteria for ME-NBI findings of SESCC. Inoue’s classification is based on the pattern of IPCLs. An alternative classification, Arima’s classification, incorporates the size of the avascular area in addition to the patterns of IPCLs [39]. In a recent study that compared these classifications, the specificity of predicted invasion depth was higher for Arima’s classification than it was for Inoue’s classification [31]. However, Arima’s classification was more complicated than Inoue’s classification, and its interobserver concordance rate was lower than that of Inoue’s classification [31]. Before our study, no report had examined the factors that influence the accuracy of ME-NBI. We found no clinicopathological factors that influenced the accuracy of ME-NBI. The rates of overestimation and underestimation were 13.0% and 10.9% for ME-NBI, which are slightly higher than those observed in a previous study [23]. In that study, the overestimation and underestimation rates of ME-NBI were 80% of the tumors included in that study were mucosal cancers. On the other hand, 50% of tumors included in our study were submucosal cancers. We believe that these differences in the proportions of mucosal
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and non-mucosal cancers account for the higher rate of underestimation in our study. Although there were no significant differences between ME-NBI and EUS in terms of sensitivities and specificities, the sensitivity and specificity rates tended to be higher for EUS. Therefore, EUS might be more suitable for identifying mucosal carcinomas that are likely to be indicated for endoscopic resection. In fact, our study showed that if both ME-NBI and EUS suggested a mucosal depth of SESCC invasion, the probability of mucosal cancer in the final histopathological assessment was very high (94%). Therefore, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection. In this manner, unnecessary endoscopic treatments could be avoided. However, before using the combination of ME-NBI and EUS in clinical practice for patients with SESCC, prospective studies are needed to evaluate the additive benefit of these techniques in predicting the invasion depth of SESCC. This study had several limitations. First, the majority of ME-NBI and EUS examinations were performed in a fixed order by the same endoscopist. Consequently, the results of ME-NBI could affect the interpretation of EUS findings. Ideally, it would be better to perform EUS and ME-NBI in a randomized order. In practice, however, it is very difficult to perform ME-NBI after EUS because the jelly used for EUS hinders detailed examinations with ME-NBI. Second, EUS and ME-NBI were performed by a single experienced endoscopist, and interobserver variation was not evaluated. Although interobserver agreement has been reported to be reliable in both EUS using a jelly-filled method and ME-NBI [15,31,40,41], interobserver variability in the assessments of EUS and ME-NBI needs to be evaluated before clinical application. In the future, a randomized, blinded crossover trial that includes the interobserver variation will be needed to determine the superior method for predicting the invasion depth of SESCC. Third, in addition to the assessment of invasion depth, EUS plays an important role in the evaluation of potential LN metastasis [13]. However, in this study, as we focused on comparing the use of ME-NBI with that of EUS for predicting the depth of tumor invasion, we used only a 20-MHz probe for EUS. Therefore, we could not evaluate LN metastasis accurately because of the limited depth of penetration of this 20-MHz probe. In conclusion, both ME-NBI and EUS provide accurate methods of predicting the invasion depth of SESCC. Their accuracies do not differ. However, when both ME-NBI and EUS suggest that the
invasion depth of the lesion is mucosal, the accuracy of the prediction is increased. Therefore, when possible, it would be better to evaluate the invasion depth of SESCC using both ME-NBI and EUS before deciding to perform endoscopic resection.
Acknowledgements This study was supported by a grant from the National R&D Program for Cancer Control, Ministry for Health, Welfare and Family Affairs, Republic of Korea (0920050) and by a clinical research grant from Pusan National University Hospital 2014. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
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